Advances in genotyping technology and statistical methods have converged to make the discovery of susceptibility genes for common diseases a reality. Genome-wide association studies (GWAS) are being performed for Alzheimer's disease (AD) and it is likely that validated loci will emerge, as impediments to the identification of genetic variants are overcome. While a major barrier is sample size, another is phenotypic heterogeneity. The discrete clinical outcome of AD diagnosis is burdened by clinical heterogeneity in the patient sample and the presence of substantial but sub-clinical AD-related pathology in control subjects. The use of quantitative intermediate phenotypes is a complementary approach that minimizes these confounders and has the potential to enhance statistical power. We are conducting an analysis of the human genome for loci associated with a quantitative measure of AD neuropathology present in two large autopsy cohorts from community-based studies, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). Polymorphisms will be secondarily evaluated for associations with cognitive decline to establish their clinical relevance. We propose to couple these human genetic studies with a simple but powerful functional screen in an existing genetic model relevant to AD in Drosophila melanogaster. This strategy will enable us to move efficiently from a list of GWAS results to validation of susceptibility genes and selection of loci for genetic fine mapping. Specifically we propose to execute the following aims: Aim 1: A GWAS for an AD neuropathology intermediate phenotype. We will perform genome-wide association analysis using data on 906,600 single nucleotide polymorphisms and 946,000 copy number probes from a pooled autopsy cohort of more than 1000 subjects. Associations will be examined for a quantitative measure of global AD pathology based on counts of amyloid plaques and neurofibrillary tangles. Aim 2: Evaluation of AD pathology susceptibility loci for associations with cognitive decline. Top-scoring polymorphisms from the GWAS will be evaluated in a pooled cohort of more than 3,800 subjects with longitudinal neuropsychiatric measures to establish their clinical relevance. This cohort will include both ROS and MAP, as well as subjects from the population-based Chicago Health and Aging Project. Aim 3: Validation of candidate susceptibility genes in a Drosopiiila model system. We will leverage the high-throughput capabilities of fly genetics, and the availability of near-saturation gain- and loss-of-function reagents for the Drosopiiila genome, to screen candidate genes identified in Aims 1 &2 for functional interactions with Tau neurotoxicity. Aim 4: Genetic fine mapping of the most promising locus. RELEVANCE: AD is the most common neurodegenerative disease and the leading cause of dementia, with nearly 13 million individuals projected to be affected in the US by 2050. Efforts to identify risk factors and develop new therapies are therefore a priority. The discovery of genes associated with AD pathology and cognitive decline will highlight novel mechanisms of disease, identify candidate drug targets, and may facilitate early diagnosis and risk prediction.